A Deprotonation Approach to the Unprecedented Amino-Trimethylenemethane Chemistry: Regio-, Diastereo-, and Enantioselective Synthesis of Complex Amino Cycles

Article abstract of DOI:10.1002/anie.201805876

The first realization of the amino-trimethylenemethane chemistry is reported using a deprotonation strategy to simplify the synthesis of the amino-trimethylenemethane donor in two steps from commercial and inexpensive materials. A broad scope of cycloaddition acceptors (seven different classes) participated in the chemistry, chemo-, regio-, diastereo-, and enantioselectively generating various types of highly valuable complex amino cycles. Multiple derivatization reactions that further elaborated the initial amino cycles were performed without isolation of the crude product. Ultimately, we applied the amino-trimethylenemethane chemistry to synthesize a potential pharmaceutical in 8 linear steps and 7.5 % overall yield, which previously was achieved in 18 linear steps and 0.6 % overall yield.

Full text of DOI:10.1002/anie.201805876

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Accepted Article
Title: A Deprotonation Approach to the Unprecedented Amino-
Trimethylenemethane Chemistry: Regio-, Diastereo-, and
Enantioselective Synthesis of Complex Amino Cycles
Authors: Barry M. Trost and Youliang Wang
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201805876
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A Deprotonation Approach to the Unprecedented Amino-
Trimethylenemethane Chemistry: Regio-, Diastereo-, and
Enantioselective Synthesis of Complex Amino Cycles
Barry M. Trost* and Youliang Wang
Abstract: Here we report the first realization of the amino-
trimethylenemethane chemistry using a deprotonation strategy to
simplify the synthesis of the amino- trimethylenemethane donor, two
steps from commercial and inexpensive materials. A broad scope of
cycloaddition acceptors (seven different classes) participated in the
chemistry, chemo-, regio-, diastereo-, and enantioselectively,
generating various types of highly valuable complex amino cycles.
Multiple derivatization reactions that further elaborated the initial
amino cycles were performed in one pot. Ultimately, we applied the
substituents.[4,5] To the contrary, the TMM donors have been
much more limited to date.[4] Of particular importance is the
absence of nitrogen substituents in TMM donors. The synthetic
potential of the amino substituted trimethylenemethane
A
(Scheme 1) to construct complex amino cycles, which are
particularly relevant to bioactive odd-membered rings[6] as
illustrated in Figure 1, motivated us to design and establish this
chemistry.
amino-trimethylenemethane chemistry to synthesize
a potential
pharmaceutical in 8 linear steps and 7.5% overall yield, which
previously was achieved in 18 linear steps and 0.6% overall yield.
Cycloadditions reactions[1] create molecular complexity
rapidly thereby leading to more step economical synthetic routes
to complex molecules, notably targets of biomolecular interest.
Indeed, the Diels-Alder reaction has had almost unparalleled
importance in the total synthesis of complex molecular targets,
notably for biological applications.[2] Access to the two key
building blocks, dienes and dienophiles, bearing many kinds of
substituents provides access to many different classes of
molecules.[2,3] Their bearing of nitrogen substituents has
particular relevance since such structural features are
particularly important for molecules of bio-
Scheme 1. Amino-trimethylenemethane and its potential precursors.
The main challenge for this discovery is how to access the
amino-trimethylenemethane intermediate A. The difficulty in
synthesizing the classical potential precursors B, C, and D
induced us to consider a deprotonation approach as developed
for the sulfonyl and cyano substituted TMM cycloadditions,[7]
although the attempts for an asymmetric version of the sulfonyl
substituted one only gave moderate diastereo- and
enantioselectivity.
substantially simplify the amino-TMM donor as
The
deprotonation
strategy
would
but
E
necessitates an acidifying nitrogen functional group with the
most obvious being nitro. The drawback of nitro, however, stems
from the ease of isomerizing allyl nitro compounds to the
conjugated nitroalkenes which could demolish reactivity. The
imino group could be a propitious alternative since the C-H bond
adjacent to the imine nitrogen can undergo deprotonation to
form 2-azaallyl anions with strong bases.[8] The amino-TMM
donor 1a (Scheme 2) could be practically synthesized from
commercial benzophenone imine and 2-methylene-1,3-
propanediol (see S.I.) and also serves as a protected primary
amine unit. Mechanistically, the pKa for the benzylic C-H bond of
N-benzyl benzophenone imine is 24.3 (DMSO) while the pKa for
the benzylic C-H bond of toluene is 41 (DMSO),[9] illustrating the
acidifying effect of the diphenylmethaneimino group. The
question posed for our design (Scheme 2(b)) now became
whether the leaving group in the TMM precursor 1a is sufficiently
basic to execute the deprotonation and whether the 2-π-
allylpalladium cation substituent in F enhances the acidity of the
C-H bond adjacent to the diphenylmethaneimino group into a
range that allows the deprotonation to occur.[10]
Figure 1. Amino cycles in biologically active natural products and drugs.
logical interest.[3] We have been involved in the development of
the cycloadditions of trimethylenemethane (TMM)[4] which
complements the types of rings produced - i.e. odd-membered
rings - where the Diels-Alder reactions typically generate even-
membered rings, notably six-membered ones. In the TMM
cycloadditions, the acceptors have tolerated a broad array of
[*]
Prof. Dr. B. M. Trost, Dr. Y. Wang
Department of Chemistry, Stanford University
Stanford, CA 94305-5080 (USA)
E-mail: bmtrost@stanford.edu
Homepage: http://www.stanford.edu/group/bmtrost
Supporting information for this article is available on the WWW
under
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Scheme 2. (a) Examples of benzophenone imine deprotonation by potassium
tert-butoxide. (b) Proposed deprotonation approach to the amino-TMM
intermediate G.
Table 1. Reaction discovery and optimization.
Entry
Ligand
Temp./Time
rt/24 h
rt/24 h
rt/24 h
rt/24 h
rt/24 h
rt/24 h
rt/4 h
Conv./Yield[a]
26%/0
dr[b]
ee[c]
1
2
-
Ph3P
-
-
100%/24%
17%/0
-
-
-
3
(PhO)3P
Bu3P
(iPrO)3P
(BnO)2PNiPr2
L1
-
-
4
25%/0
-
5
100%/73%
51%/30%
100%/75%
100%/70%
100%/99%
100%/99%
10/1
-
-
6
-
7
>20/1
10/1
>20/1
>20/1
-10%
12%
92%
94%
8
L2
rt/4 h
9
L3
rt/4 h
10
L3
4 °C/4 h
[a] 0.15 mmol scale, isolated yield. [b] Determined by crude 1H-NMR analysis.
[c] Determined by chiral HPLC.
With the above questions in mind, we probed the prospect of
a TMM reaction with 1a using nitroolefins as acceptors, in part
because of the broad versatility of the nitroolefins and a route to
polyamino ring systems (Figure 1). The reaction optimization
results are summarized in Table 1. In addition to stereoisomers,
there are 3 different regioisomers (3a, 4, 5) that could form as
well. For racemic reactions, a phosphine ligand proved critical
for reactivity (entry 1-6), with triisopropylphosphite optimal to
give 73% yield and 10/1 dr (entry 5). Effort was then turned to
realize this [3+2] process enantioselectively by using chiral
phosphine ligands. The diamidophosphite ligand L1[11] gave a
moderate yield but low ee (entry 7). Encouragingly, a rather
simple chiral phosphoramidite ligand L2 provided similar yield
and ee (entry 8). A more complex phosphoramidite ligand L3
was then employed (entry 9). Much to our delight, the ee was
dramatically enhanced from 12% to 92% and the yield and
diastereoselectivity were also improved remarkably. Lowering
the reaction temperature further improved the ee (entry 10). It is
worth noting that this [3+2] process was not only diastereo- and
enantioselective but also regioselective. Product 3a was
generated as the only product while the other regioisomeric
products 4 and 5 were not detected.
Scheme 3. Scope of disubstituted trans-nitroolefins.
With the optimized conditions in hand, we studied the scope
of the amino-TMM chemistry. Nitroolefins were systematically
examined (Scheme 3, 4). Electron rich, electron neutral, and
sterically bulky nitrostyrenes participated in the [3+2] reaction
with excellent yield, dr, and ee values, while the electron poor
ones gave moderate yield (3b-3i). Several heteroaromatics were
tolerated (3j-3l). Conjugated 1,3-nitrodienes cyclized with 1a in a
selective [3+2] fashion (3m-3n). Moreover, nitroethylenes with
various alkyl substituents (primary, secondary, and tertiary) were
suitable cycloaddition partners (3o-3u). The benzophenone
imine substituted nitroethylene 2v and the phthalimide
substituted one 2w facilely coupled with amino-TMM donor 1a,
yielding cyclopentane structures with three contiguous chiral
amine functionalities, which constitute the core structures of
jogyamycin, pactamycin, and agelamadin B.[6d-f] The cyclization
between amino-TMM and trisubstituted nitroolefins proceeded
smoothly, generating quaternary and tetrasubstituted chiral
carbon centers (Scheme 4). The dearomatative cycloaddition
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with 5-nitroisoquinoline 2aa resulted in excellent ee as well as
moderate yield and dr.
Scheme 4. Scope of trisubstituted nitroolefins.
Scheme 6. One pot amino-TMM cycloaddition – elaboration.
Scheme 7. Derivatization of the amino-TMM products via the Pictet-Spengler
reaction.
The mild conditions of the initial amino-TMM reaction
allowed various derivatization reactions to be conducted in one
pot, which further elaborated the [3+2] cycloadduct (Scheme 6).
For instance, addition of 1 N aqueous hydrochloric acid to the
TMM reaction solution hydrolyzed the benzophenone imine
moiety to give primary amine 6. Reduction of the nitro group by
adding SmI2 to the reaction mixture provided 7 with two
orthogonal amino groups. The nitro group of 3a acidifed the
adjacent hydrogen to form tertiary nitrogen substituted centers.
Scheme 5. Scope of other classes of acceptors.
Gratifyingly, the scope of this amino-TMM reaction is not
limited to nitroolefins. Other types of electron deficient
A
base catalyzed Michael addition to methyl acrylate, a
π
palladium-catalyzed allylic alkylation, or a Barton arylation with
an aryl BiV reagent[13] all proceeded with high diastereoselectivity,
leading to compounds 8, 9, and 10 respectively. Furthermore,
the exocyclic double bond of 3a could be functionalized via a
diastereoselective dihydroxylation reaction to generate
aminocyclitol 11. The juxtaposition of the amine group to the aryl
group of the nitrostyrene type substrates enabled the Pictet-
Spengler reaction to access piperidines (Scheme 7). For
example, the TMM adduct 3y was hydrolyzed then
formaldehyde was added to provide the Pictet-Spengler product
12 in 71% overall yield as a single regio- and diastereoisomer.
Unexpectedly, under the same hydrolysis conditions, the
benzophenone imine moiety of 3j was not hydrolyzed but
cyclized to the pyrrole ring to form the Pictet-Spengler product
13 in 80% yield.
acceptors such as α,β-unsaturated carbonyl compounds reacted
efficiently (Scheme 5). The azlactone acceptor 2dd provided
access to unusual α-amino acids. The pyrone 2ee underwent
[3+2] cyclization and the tropone 2ff gave exclusive [3+6]
product. Imine served as an excellent partner in this chemistry
thereby extending the method to access amino substituted
pyrrolidines (3gg). In all cases, the corresponding cycloadducts
were isolated in good yield and ee. The absolute stereochemical
assignment for all the cycloadducts derives from the x-ray
structure of the product 3i.[12]
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Maclaren (Stanford University) for X-ray crystallographic
analysis.
Conflict of interest
The authors declare no conflict of interest.
Keywords: palladium • trimethylenemethane • asymmetric
catalysis • cycloaddition • amine
Scheme 8. Application of the amino-TMM chemistry to drug molecule
synthesis.
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The synthetic utility of the above amino-TMM chemistry was
further highlighted by its application to the synthesis of the drug
candidate 17, which was patented by Abbott Laboratory[6b] (now
Abbvie). In their patent, an 18-step linear synthesis was
implemented in 0.6 % overall yield. With this amino-TMM
chemistry, we could formally synthesize it in 8 linear steps (10
total steps) and the overall yield was improved to 7.5 % at
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a
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14 was achieved in presence of the nitro and the benzophenone
imine group. Subsequently, the imine moiety was hydrolyzed in
one pot to release the primary amine, which was in situ
protected with di-tert-butyl dicarbonate (Boc2O) to give 15. The
nitro group of 15 was reduced to primary amine and protected
with benzyl chloroformate (CbzCl) in situ. Ultimately, the primary
alcohol was oxidized into the carboxylic acid 16 using Jones’
reagent. According to the Abbott synthesis[6b], the desired drug
candidate 17 could be obtained in one step from 16.
In summary, an important missing piece of the TMM story
has been resolved – for the first time a TMM donor bearing an
amino surrogate has been created. The availability of the amino-
TMM donor in 2 steps from commercial subunits enhances the
practicality. Most striking is the exceptional reactivity that this
amino-TMM donor possesses which leads to a very broad scope
of the method. The effectiveness of this substituent is also
indicated by the ability of the simple Feringa phosphoramidite
ligand L3 to induce high level of enantioselectivity while in the
the parent TMM and cyano substituted TMM chemistry the same
ligand only provided low to moderate enantioselectivity.[5] This
development came about from an underutilized deprotonation
approach in TMM chemistry. The results show that the
deprotonation approach to TMM proceeds with exceptional
regio-, diastereo-, and enantioselectivity as does the desilylative
approach[4b] – a fact that suggests the two approaches might
proceed through similar types of intermediates. Furthermore, the
mildness of the reaction conditions allows multiple additional
processing of the initial adducts in a one pot fashion from the
reactants of the TMM cycloaddition reaction. This
accomplishment sets the stage to access biologically active
targets with complex amino cycles.
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Acknowledgements
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[12] CCDC 1843270 contains the supplementary crystallographic data for
this paper. These data are provided free of charge by The Cambridge
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We thank the NSF (CHE-1360634) and the NIH (GM033049) for
financial support of our programs. We acknowledge S. R. Lynch
(Stanford University) for his help with two-dimensional nuclear
magnetic resonance analysis. We also acknowledge Dr. Jana
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Entry for the Table of Contents (Please choose one layout)
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Barry M. Trost* and Youliang Wang
Page No. – Page No.
A Deprotonation Approach to the
Unprecedented Amino-
Trimethylenemethane Chemistry:
Regio-, Diastereo, and
Enantioselective Synthesis of
Complex Amino Cycles
Nitrogen on TMM donor: A novel trimethylenemethane (TMM) donor with nitrogen
substituent has been developed. The generation of the palladium-TMM complex
relies on an underutilized deprotonation strategy. It reacted with various types of
α,β-unsaturated π acceptors in a regio-, diastereo-, and enantioselective fashion.
The cycloaddition products are highly valuable amino cycles, which can be readily
derivatized and applied to drug molecule synthesis.
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